Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in the art.
The cervix is the lower, narrower portion of the uterus where it joins with the top end of the vagina. The exposed portion of the cervix that projects into the vagina is called the exocervix or ectocervix. The opening of the ectocervix is called the external os. Between the uterine cavity and the external os is a passageway known as the endocervical canal or the endocervix.
Generally two types of epithelium occur along the cervix. The position or location of these types may change due to cervical remodelling that occurs, for example, during puberty, menopause, pregnancy and child birth and the normal menstrual cycle.
In general, the ectocervix is covered by stratified squamous epithelium, whereas the endocervix is covered by simple columnar epithelium. The “squamocolumnar junction” is a region where the squamous epithelium is juxtaposed with the columnar epithelium. During times of cervical remodelling, the columnar epithelium of the endocervix may extend into the harsh acidic environment of the vagina and undergo metaplasia to hardier squamous epithelium. In turn, when the squamous epithelium regresses into the endocervical canal, the squamous epithelium is replaced by simple columnar epithelium. The area between the original squamocolumnar junction and the new squamocolumnar junction is termed the “transformation zone” (Rubin and Farber “Pathology”. J.B. Lippincott Company 1988. Page 956). In teenage girls, the transformation zone is on the immature cervix's outer surface and is more susceptible to infection than in adult women. In older women, the transformation zone may be higher in the cervical canal.
Ectocervical epithelium consists of 4 layers: basal cells on the basal membrane; parabasal cells between the basal cell layer and the mature cell layers; a layer of intermediate, polygonal and mature cells; and superficial cells. A layer of exfoliating cells may also be seen in histological sections. Underneath the basal membrane is the connective tissue. The endocervical epithelium in contrast is a layer of columnar epithelium composed of mucin secreting cells on top of the connective tissue. The endocervical canal may contain crypt or crypt-like structures.
The transformation zone is itself particularly vulnerable to the effects of infections, the most well known one being infection with human papillomavirus (HPV). It has been estimated that 325 million women have either subclinical HPV or HPV-related clinical lesions. The presence of persistent HPV infection is thought to be a prerequisite for the development and maintenance of second and third stage cervical intraepithelial neoplasia (CIN II-III), i.e. severe or precancerous dysplasia. Cervical intraepithelial neoplasia (CIN) can be either squamous or glandular in origin, but squamous intraepithelial neoplasia (IN) is more common. CIN I represents mild IN and the cell abnormalities are confined to the basal ⅓ of the epithelium. CIN II is moderate IN confined to the basal ⅔ of the epithelium and CIN III is severe IN that spans more than ⅔ of the epithelium, possibly the full thickness.
Of the genital types affecting humans, the high-risk types such as HPV 16, HPV 18, HPV 45 and HPV 31 are linked to the development of low and high-grade dysplasia and cervical cancer. Oncogenic strains of HPV have been found in 99.7% of cervical cancers. They are also associated with vulval, anal and penile carcinoma. Low risk types such as HPV 6 and HPV 11 are associated with genital warts and low-grade IN.
Current treatment of severe uterine cervical IN is by surgically removing the areas of the uterine cervix that may possibly be involved. Treatment initially requires cytology, colposcopy and biopsy, and then a surgical treatment such as laser excision, loop excision or cold coagulation of the uterine cervix. These more radical treatments however are associated with increased risk of complications including cervical stenosis, constriction and complete sealing of the os, pelvic endometriosis following hematometra, painful and prolonged menstruation, excessive eversion of columnar epithelium, infection, bleeding, pain, psychological morbidity, infertility, and an incompetent cervix. And even after treatment, disease may recur and even progress to invasive cancer. Pre-term delivery is now also recognised as a complication.
In contrast, there is currently no reliable and effective treatment available for women who have been diagnosed with an HPV infection, usually during their routine Pap smears, but are asymptomatic or only have low grade lesions. The routine practice is to simply monitor the woman for signs of progression. This approach however is unsatisfactory for at least two reasons:
1. Some women are distressed by having Pap smear abnormalities even though they are not considered to be serious. In order to alleviate their concerns, many women with low-grade lesions undergo unnecessary treatment with the more radical methods reserved for severe IN.
2. In the absence of treatment, it is more difficult to ensure that the woman attends for further follow-up and monitoring for possible progression to high-grade disease.
There is therefore a need for a treatment of early stage infection before complications of infection occur. This treatment needs to be less invasive and radical than those currently available for the treatment of later stage disease.
In light of the vastness of the problem of HPV infection world wide, research has focused on prevention. This focus has seen the successful development of two vaccines—Cervarix™, manufactured by GlaxoSmithKline, and Gardasil™ by Merck & Co. Cervarix™ is created using proteins of the HPV viral capsid, which once administered, induces the formation of neutralizing antibodies. In addition, Cervarix™ is formulated with AS04, a proprietary adjuvant that has been reported to boost the immune system response for a longer period of time by increasing the humoral immune response and increasing the number of immune memory B-cells (Vaccine 24, 14 Aug. 2006). AS04 is an adjuvant which is a combination of standard aluminium hydroxide and 3′-deacylated monophospholipid A (MPL—Corixa, Mo., USA), a derivative of the lipid A molecule found in gram-negative bacteria and a potent immune system stimulant.
Vaccines such as these however have two key limitations. The first is that Cervarix™ and Gardasil™ are both preventative vaccines, not therapeutic, and will therefore have no effect on already established infections. The second limitation is that HPV immunity is type-specific. So while these vaccines will block infection with the most common cancer causing HPV strains, vaccination with current vaccines will not completely block infection from cervical cancer-causing HPV strains other than HPV 16, 18, and in the case of Cervarix™, HPV 31 and 45 as well.
An object of the invention therefore is to endeavour to reduce the complications of HPV infection, the incidence of uterine cervical dysplasia (all stages) and cervical cancers, and to avoid more radical treatments by early treatment of infection.
It is understood that other tissues having transformation zones may also be more vulnerable to infection and would benefit from a treatment for early stage infection. The anus for example is also particularly vulnerable to the effects of HPV infection at the transformation zone where the stratified squamous cells of the anal verge change over to the columnar epithelial cells of the rectum. Current treatment for anal IN is either surgical removal or, in many cases, observational if severe focal or multi quadrant infection is present. It is observational in many cases where not extensive. If the dysplasia is very severe and involves the whole circumference of the anal canal, surgical treatment is to remove the whole area and provide a colostomy. Because the operation is so radical, and the duration of time to progress from anal dysplasia to anal cancer is not known, an observational approach is usually undertaken and the individual treated when cancer arises. This is obviously an unsatisfactory approach for individuals with early stage infection, who must simply sit back and wait to see if they develop cancer or other complications of HPV infection.
Other tissues susceptible to metaplasia and having transformation zones include the throat, where columnar epithelium is replaced by squamous epithelium, the oesophagus, where squamous epithelium is replaced by columnar epithelium, and the urinary bladder, where transitional epithelium is replaced by squamous epithelium.
It is also understood that infections of transformation zones may be by micro-organisms other than HPV. Other infections may include viral infection with herpes simplex virus (HSV), bacterial infections with Chlamydia trachomatis, Haemophilus ducreyi, Mycoplasma hominis, Mycoplasma genitalium, Streptococcus Sp, Escherichia coli, Staphylococcus, and Neisseria gonorrhoeae, fungal infections caused by an overgrowth of Candida albicans and other Candida species, protozoan infections with Trichomonas vaginalis. 
In light of the different tissues that may require treatment of infection of the transformation zone, and the different micro-organisms that may be the infective agent, there is a need for a treatment that has broad application.